Carbapenem-resistant Enterobacteriaceae (CRE) and methicillin-resistant Staphylococcus aureus (MRSA) increase patient morbidity and mortality. CRE are emerging pathogens with a predilection for ICU patients. MRSA also is extremely prevalent, leading to a large number of patients in the United States being placed on contact precautions for MRSA. Contact precautions prevent the spread of antibiotic-resistant bacteria in the acute-care setting. However, contact precautions may also have adverse effects, including a decreased frequency of healthcare worker visits, increased psychological symptoms of patients, and potentially more serious adverse events. What is not known is if certain patients are more likely to transmit antibiotic-resistant bacteria to healthcare workers and subsequent patients, and if so, what characteristics identify these patients. In addition, what is not known is which healthcare worker-patient interactions lead to greater transmission and which bacterial-specific factors lead to increased transmission. The overall objective of this proposal is to explore factor associated with transmission of these bacteria and potential biomarkers to help determine which patients with CRE and MRSA should be placed on contact precautions, which may need enhanced precautions, and which may not need contact precautions. The proposed research is feasible because we have experience and have published using all of the methodologies proposed. Our hypothesis is that certain patient characteristics and certain healthcare worker-patient interactions lead to higher transmission and that the individual risk factors identified wil be unique for CRE and MRSA. We plan to test our central hypothesis and, thereby, accomplish the objective of this application by pursuing the following three specific aims: Aims 1 and 2: We will perform a multi-site, diverse geographic region cohort study to determine which patient risk factors and healthcare worker-patient interactions lead to greater transmission of CRE (aim 1) and MRSA (aim 2). Aim 3: We will perform whole genome sequencing on stored specimens obtained in aims 1 and 2 for high- transmission bacteria and low-transmission bacteria to determine molecular properties of the bacteria that result in observed differences in transmission. The significance of the proposed work is that it will lead to greater understanding of the factors associated with transmission of these bacteria, identifying high risk activities and provide biomarkers to help determine which patients with CRE and MRSA should be placed on contact precautions, which may need enhanced precautions, and which may not need contact precautions. This proposal is innovative for the following reasons: a) It explores the novel concept of superspreaders of antibiotic-resistant bacteria, which has been suggested previously, but never studied in depth; b) The surrogate outcome of culturing healthcare workers hands and gloves upon room exit greatly increases the power of the study and is a near-perfect surrogate outcome for patient transmission; and c) This outcome choice allows the study to be done in a cost-effective manner on a smaller scale.